ASTRO: Antibody Prevents Radiation-Induced Fibrosis in Mice

Action Points

Explain to interested patients that lung cancer is difficult to treat with radiation because of radiation-induced damage to the lung.

Note that this study suggests blocking a chemical messenger may prevent and even reverse radiation-induced fibrosis, at least in animals.

This study was published as an abstract and presented orally at a conference. These data and conclusions should be considered to be preliminary as they have not yet been reviewed and published in a peer-reviewed publication.

LOS ANGELES, Oct. 31 -- Blocking a chemical messenger can prevent some of the lung damage caused by radiation therapy, at least in experimental animals, a researcher said here.

The same approach also halted fibrosis after the onset of disease, Dr. Cheng told researchers at the American Society for Therapeutic Radiation and Oncology meeting.

The approach hasn't been tested in humans, Dr. Cheng noted, but if it works it could help eliminate one of the barriers to successful radiation treatment of lung cancer -- the toxicity of radiation.

Dr. Cheng noted that up to 70% of people treated with radiation for their lung cancer will have radiographic evidence of fibrosis, usually occurring several weeks to months after therapy, and 15% will display symptoms such as cough and shortness of breath.

In a series of experiments, Dr. Cheng and colleagues gave mice a high dose of 14 Gray of radiation to the lungs to induce fibrosis.

Some of the mice lacked the gene for a protein called integrin beta-6, which activates TGF-beta, and they were shown to be immune to radiation-induced fibrosis, he said.

Normal animals, on the other hand, developed fibrosis in about 17% of their lungs, on average, when they were examined 27 weeks after the radiation exposure.

Next the researchers exposed normal mice to the radiation dose and 15 weeks later injected them with varying doses of a monoclonal antibody that blocks integrin beta-6.

For that experiment, control mice were injected with immunoglobulin G and 35 of 42 developed histologically evident areas of fibrosis, Dr. Cheng said.

On the other hand, there was dose-dependent protection for treated mice. Twenty-five of 42 of those getting the lowest dose developed fibrosis, compared with nine of 41 getting the highest dose.

The researchers also found that giving the antibody after the onset of disease halts the process in its tracks, he said.

"People have thought you'd have to [treat for fibrosis] at the time of radiation," Dr. Cheng said. "But instead of the shotgun approach, we could just treat people who need it."

Blocking TGF-beta can cause inflammation in the lungs, he said, but the therapeutic dose of the antibody is low enough that inflammation does not result.

In a similar study presented at the same ASTRO plenary session, researchers from Virginia Commonwealth University and Duke University in Durham, N.C., showed that blocking TGF-beta with an orally administered small molecule reduced breathing difficulties and weight loss in rats after a 28 Gray dose of radiation.

Taken together, the two studies offer the possibility of solving a "vexing issue in lung cancer," commented Ramesh Rengan, M.D., Ph.D., of the University of Pennsylvania in Philadelphia, who was not involved in either study.

In non-small-cell lung cancer, Dr. Rengan said, radiation oncologists face a dilemma: "You have a very radio-resistant tumor embedded in a very radio-sensitive organ -- and that organ is a vital organ."

"You are faced with an uphill battle from the beginning," he said.

Dr. Rengan said the study from Dr. Cheng and colleagues provides proof that TGF-beta is "involved front and center in playing an active role in inducing" fibrosis.

The antibody and the oral small molecule tested by the Duke group are potentially ways to block the effect, he said, with the caveat that "what works in mice oftentimes doesn't work in humans."

Both studies were partly supported by Biogen, and two co-authors of the second study were employees of Biogen. Dr. Cheng reported no conflicts.

Reviewed by Zalman S. Agus, MD Emeritus Professor at the University of Pennsylvania School of Medicine